Methods of inhibiting proinflammatory neuroimmune signaling and treating inflammatory disorders

Abstract

Methods of inhibiting proinflammatory neuroimmune signaling as is related to the treatment of inflammatory disorders are provided. These methods include the inhibiting of toll-like receptor signaling and/or the enhancement of anti-inflammatory signaling, and in one example, the inhibiting of TLR2, TLR4 or TLR7 signaling as well as the enhancement of fracktalkine or IL-10 signaling either alone or together.

1 . A method for treating a TLR-mediated inflammatory condition in a subject, comprising administering to the subject a neurosteroid, wherein the inflammatory condition is either not a neuropsychiatric disorder, or is a neuropsychiatric disorder that is non-responsive to GABAergic drugs. 
     
     
         2 . The method of  claim 1 , wherein the neurosteroid is pregnenolone, (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP), or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the neurosteroid is an inhibitor of toll-like receptor signaling or corticotropin (CRF) releasing hormone signaling. 
     
     
         4 . The method of  claim 3 , wherein the neurosteroid is an inhibitor of TLR2, TLR4 or TLR7 receptor signaling. 
     
     
         5 . The method of  claim 1 , wherein the TLR-mediated inflammatory condition is a neuropsychiatric disorder that is non-responsive to GABAergic drugs. 
     
     
         6 . The method of  claim 1 , wherein the TLR-mediated inflammatory condition is selected from the group consisting of sepsis, gastrointestinal disease, chronic obstructive pulmonary disease (COPD), asthma, and atherosclerosis. 
     
     
         7 . The method of  claim 1 , wherein the TLR-mediated inflammatory condition is selected from the group consisting of pain, stroke, seizure, alcohol detoxification, Alzheimer's disease, and dementia. 
     
     
         8 . The method of  claim 1 , further comprising assaying a sample from the subject for TLR signaling in peripheral blood mononuclear cells or cerebrospinal fluid, wherein decreased TLR signaling is an indication of a therapeutically effective amount of neurosteroid. 
     
     
         9 . The method of  claim 1 , further comprising increasing the amount of neurosteroid administered to the subject if decreased TLR signaling in the peripheral blood mononuclear cells or cerebrospinal fluid is not detected. 
     
     
         10 . A method for treating a neuropsychiatric disorder in a subject in need thereof comprising
 (a) detecting in a sample from the subject elevated levels of one or more of MCP-1, TNF-α, pIRF7 and HMGB1, pIRF7, and INFs; decreased levels one or more of fracktalkine and IL-10; or any combination thereof; and   (b) administering to the subject a therapeutically effective amount of a neurosteroid.   
     
     
         11 . The method of  claim 10 , further comprising monitoring samples from the subject for levels of fracktalkine, IL10, MCP-1, TNF-α, pIRF7 and HMGB1, pIRF7, INFs, or any combination thereof. 
     
     
         12 . The method of  claim 10 , wherein the neuropsychiatric disorder is a chronic neuropsychiatric disorder. 
     
     
         13 . The method of  claim 10 , wherein the neuropsychiatric disorder is selected from a group consisting of cognitive disorders, seizure disorders, movement disorders, traumatic brain injury, secondary psychiatric disorders, substance-induced psychiatric disorders, attentional disorders, and sleep disorders. 
     
     
         14 . The method of  claim 10 , wherein the neuropsychiatric disorder is alcoholism. 
     
     
         15 . A method for identifying inhibitors of proinflammatory neuroimmune signaling comprising measuring of inhibition of MD-2 binding to TLR4 in the presence of a candidate compound, wherein the inhibition of MD-2 binding to TLR4 by a candidate compound is indicative that the candidate compound is an inhibitor of proinflammatory neuroimmune signaling. 
     
     
         16 . The method of  claim 15 , wherein the candidate compound is a neurosteroid, or a modification, variant, derivative, or analog thereof. 
     
     
         17 . The method of  claim 15 , wherein the inhibition of MD-2 binding to TLR4 is measured by immunoprecipitation. 
     
     
         18 . The method of  claim 15 , wherein the method further comprises measuring of inhibition of upregulation of any one of, any number of, or all of, pTAK1, TRAF6, NFκB p50, phospho-NF-κB-p65, pCREB, HMGB1, MCP-1, p-IRF7, INFs and TNFα.